CZ279793A3 - Orally active antiviral compounds - Google Patents

Abstract

A compound represented by formula I Ar1-O-M-O-Ar2 I wherein Ar1 and Ar2 are independently substituted phenyl or substituted pyridinyl, the substituents on said phenyl or pyridinyl being independently selected from one, two or three of (C1-C10) alkyl, (C1-C10) alkoxy, halogen, carbamyl, dialkylcarbamyl, (C1-C10)-alkoxycarbonyl, oxazoyl, and (C1-C10) alkyl substituted by halogen, (C1-C10) alkoxy, hydroxy, or (C1-C10) alkoxycarbonyl; <CHEM> (C4-C8) alkylene, (C4-C8) alkenylene or (C4-C8)- alkynylene; O is oxygen; R min is (C1-C3) alkyl or H; A is oxygen or sulfur; Q is selected from hydrogen, halogen, nitro, (C1-C6) alkyl, (C1-C6) perhaloalkyl, (C1-C6) alkylthio (C1-C6) alkyl sulfonyl; the dotted lines in M-3 and M-4 between carbons 2, 3 and 4, and 5 and 6 mean that the bonds between carbons 2 and 3, and 3 and 4, and 5 and 6, may each be a single or double bond; n = 1 or 2 m = 1 or 2 p = 0 or 1 and or pharmaceutically acceptable salts thereof. as well as pharmaceutical compositions containing the compounds and the use of the compounds of formula I for preparation of a medicament for methods of treating or preventing viral infections, especially picornaviral infections, are disclosed.

Description

Orally active antiviral compounds

Technical field

The present invention relates to compounds having antiviral activity, to pharmaceutical compositions containing these antiviral compounds and to the use of such compounds for the preparation and / or prevention of viral infections and methods of treating and / or preventing viral infections, particularly picornavirus infections, in mammals using of these pharmaceutical preparations.

BACKGROUND OF THE INVENTION

US Patent 4851423 and related European Patent Application No. 0274867, published July 20, 1988, generally disclose compounds having antiviral, anti-inflammatory and platelet activating factor inhibiting activity. The related European patent application describes compounds which are represented by the following structural formulas I and II

ZXQYW (I) ZXQY-W'-YQXZ (Ii) and pharmaceutically acceptable acid, base, and quaternary amine salts thereof, and pharmaceutically acceptable solvates thereof, wherein each Z is independently tertiary butyl, phenyl, naphthyl or adamantyl substituted phenyl, wherein the substituents are one or more halogens, lower alkoxy, phenoxy, nitrile, nitro, phenylsulfonyl, lower alkylsulfonyl, oxazol-2-yl, lower alkanoyl, benzoyl, lower alkoxycarbonyl, lower alkyl, phenyl, lower alkylthio, phenylaminothiocarbonyl, or a lower alkylaminothiocarbonyl of a 4-6 membered unsubstituted or substituted heterocyclic ring containing at least one ring nitrogen with the remaining ring members being at least one ring and optionally sulfur

-2 or oxygen wherein the substituents are one or more -COOH, -CH 2 OH, lower alkyl, lower alkylcarbonyl, or aryl-lower alkyl,

X and Y independently are bonds, -O-, -3-, -SO2NHOH OH, O

U Μ H H J »1

-N-, -N-C-, -C-, -O-, -C-;

each Q is independently divalently substituted or unsubstituted, straight or branched lower alkanediyl, lower alkanediyl-cycloalkanediyl-lower alkanediyl, lower alkanediyl, lower alkindiyl, phanylene, dihydrofurandiyl, tetrahydrofurandiyl, tetrahydropyrandiyl, lower alkanediyltetrahydrofuranediandi, or more hydroxy, epoxy, fluorine, chlorine, azido or amino,

W is a monovalently substituted or unsubstituted aryl group or a heterocyclic single or fused ring containing from 4 to 10 ring atoms, wherein at least one heteroatom is a nitrogen atom and the remaining ring atoms form at least one carbon atom and optionally sulfur or oxygen, wherein the substituents are one or more hydroxy, oxo, amino, carbamoyl, carboxyl nitrile, nitro, lower alkyl, lower alkyloxycarbonyl, halogen, sulfamyl, lower alkoxycarbonyl-lower alkyl, lower alkylthio, lower alkoxy, hydroxy-lower alkyl, amino-lower alkyl, carboxy lower alkyl , guanidino, thioureido, lower alkylsulfonylamino, aminocarbonyl-lower alkyl, alkoxycarbonylmethyl or carbamoyloxy lower alkyl with the proviso that W cannot be substituted or unsubstituted isoxazolyl,

W * is divalent * ».

However, the compounds of the present invention have not been specifically described.

3. Summary of the Invention

The present invention provides compounds of Formula I

Ar -OMO-At (X) wherein Ar 1 and are independently substituted phenyl or substituted pyridinyl, wherein the substituents of said phenyl or pyridinyl are independently selected from the group consisting of one, two or three (C 1 -C 6 alkyl, (C 1 -C 6 perhaloalkyl, (C ₁ -C ₆ ) alkoxy, halogen, carbamyl, di (C 1 -C 6) alkylcarbamyl C 1-6 alkoxycarbonyl, oxazolinyl and C ₁ -C 6 alkyl substituted by alkoxy, hydroxy or (C ₁ -C 6) alkyl; (-C1-6) alkoxycarbonyl,

(C ₄ -C _g) alkylene, (C ₄ -C _g) alkenylene or (C ₄ -C _g) aikinylen,

-40 is oxygen,

R * is (C 1 -C 6) alkyl or H,

And is oxygen or sulfur,

C is selected from the group consisting of hydrogen, halogen, nitro, (C 1 -C 8) alkyl, (C ₁ -C 8) perhaloalkyl, (C 1 -C 8) alkylthio and (C 1 -C 8) alkylsulfonyl, dashed lines in ΰΛ — 3 and M-4 between carbons 2 and 3, 3 and 4 and 4 and 5 mean that the bonds between carbons 2 and 3, 3 and 4 and 4 and 5 can each be a single or double bond, n is 1 or 2, m is 1 or 2 , p is 0 or 1, or a pharmaceutically acceptable salt thereof.

In a preferred embodiment, the present invention provides compounds of formulas II or III _Ia -OMO-Ar _1b

_An AP -0-M-0-te _2b (II) (III) wherein Ar @ ₁ and Ar _and & are independently selected from the group consisting of phenyl, substituted by one, two or three (C ^ -Cg) alkyl, ( C 1 -C 6 perhaloalkyl, (C ₁ -C ₆ ) alkoxy, halogen, oxazolinyl, carbamyl, C ₁ -C ₆ alkylcarbamyl (C ₁ -C ₆ ) alkyl substituted with (C ₁ -C 8) alkoxy, hydroxy or (C ₁ -C 8) alkoxycarbonyl,

or with three (C 1 -C 8) alkyl, γ, (C ₁ -C 8) perhaloalkyl, (C 1 -C 8) alkoxy, halogen, oxazolinyl, carbamyl, di (C 1 -C 8) alkylcarbamyl, (C 1 -C 8) -alkyl substituted with (C 1 -C 8) alkyl; -Cg) -5alkoxylem, hydroxy or _(C1 -Cg) alkoxycarbonyl

CHg /

CHa · (CR'R ') p (CR'R') p

AND

(CHzJn

M-3

M-4 (C1-C6-alkenylene or (C1-C6) alkynyl,

O is oxygen,

R ^z * ge (C 1 -C 3) alkyl or H ',

And is oxygen or sulfur,

Q is selected from the group consisting of hydrogen, halogen, nitro, (C 1 -C 6) alkyl, (C ₁ -C ₆ ) perhaloalkyl, (C 1 -C 6) alkyl-f, thio and (C 1 -C 6) alkylsulfonyl; / the dashed line in M-3 and M-4 between atoms 2 and 3, 3 and 4 / ΐ— and 4 and 5 means that the bonds between atoms 2a, 3, 3 and 4 and 4 and 5 can each be a single or double bond , n is 1 or 2, m is 1 or 2, p is 0 or 1, or a pharmaceutically acceptable salt thereof.

The present invention also provides a pharmaceutical composition for the treatment of viral infections comprising an antiviral effective amount of a compound of Formula II, II or III and a pharmaceutically acceptable carrier. Preferred are pharmaceutical formulations adapted for oral administration of a compound of the invention.

The present invention further provides the use of a compound of formula I, 11 or III for the preparation of a medicament for the treatment of viral infections in a mammal afflicted with a viral infection.

The present invention further provides a method of treating and / or preventing a picornavirus infection in a mammal in need of such treatment or prevention comprising administering to said mammal an antipicornavirus effective amount of a compound of Formula I, II or III or a pharmaceutical composition comprising such a compound.

It has been found that the compounds of the present invention, as compared to the prior art compounds, have excellent antiviral activity, exhibit oral activity and a broad spectrum of antiviral activity.

Some of the compounds of the invention may exist in isomeric forms due to the presence of a double bond or one or more chiral centers. All such isomers both in pure form and as a mixture, including racemic mixtures, are considered to be part of the present invention.

The compound of the present invention has been found to be active against ether-resistant RNA viruses, i.e. picornaviruses, including enteroviruses and rhinoviruses. Enteroviruses include poliovirus, coxsakieviruses and echviruses. Rhinoviruses include viruses associated with common cold and certain other renal disease. The compounds of the present invention have been found to be active against a large number of enteroviruses, including poliovirus-2, coxsackieviruses A9, A21 and 31, and Echo 4.6 and 11, respectively.

The compounds of the invention were found to be active against individual rhinoviruses such as rhinovirus 1A, 1.14 and 86. Representative compounds of the invention were further found to exhibit oral activity in a murine poliovirusencephalitis model. They are prepared by synthesis from commercially available or readily available starting materials.

The term "substituted phenyl" means phenyl substituted by one, two or three substituents independently selected from the group consisting of halogen, (Cj-Cj _Q) -alkyl, (C ₁ oíperhalogenalkyl, (C ₁ -C ₁ θ) alkoxy, carbamyl, dialkylcarbamyl (C ₁ -C 6) alkoxycarbonyl, oxazolinyl, and (C 1 -C 6) alkyl substituted with halogen ·, (C ₁ -C ₆ ) alkoxy, hydroxy or (C ₁ -C ₆ ) alkoxycarbonyl.

Preferred substituted phenyl includes phenyl substituted with two substituents selected from the group consisting of (C ₁ -C 8) alkoxy such as methoxy and ethoxy and halogen such as Cl and F. More preferred substituted phenyl, y include phenyl substituted with two methoxy, chloro, fluoro or methyl , like the following groups:

The term (C 1 -C 6) alkyl means straight and branched (C 1 -C 10) alkyl groups such as methyl, ethyl, n and iso-propyl, iso-, sec- and tert. butyl, η-, sec-, iso-, tert- and neopentyl, η-, sec- iso-, tert. and neo-hexyl and the like.

The term "’ (C 1 -C 6) alkoxy "means straight and branched (C 1 -C 6) alkyl groups linked by a single bond to divalent oxygen. *

-9Výraz _(C1-θ) perhalogenalkvl "refers to straight and branched chain alkyl groups having one to ten carbon atoms wherein víechny hydrogens are replaced by halogen, especially by fluorine or chlorine or mixtures thereof. The use of (C 1 -C 6) perhaloalkyl is preferred, more preferably the use of (C 1 -C 6) perhaloalkyl, eg, trifluoromethyl.

Expression

The term halogen includes fluorine, chlorine, bromine and iodine. O

H carbamyl means 1H-N-C-.

The term "di (C ₁ -C ₁₀ ) alkylcarbamyl" means that the two hydrogens in the dialkylcarbamyl are replaced by C ₁ -C ₆ -alkyl groups, with diCG ₁ -C ₆ -alkylcarbamyl being preferred.

The term (C ₁ -C 6) alkoxycarbonyl ^M means (C ₁ -C ₆ ) alkoxy monovalently attached to a carbonyl.

The term oxazolinyl means

ýraz ^ (C ^ C) alkyl substituted with (C ₁ -CjθJalkoxy, hydroxy or (G ₁ -G ^ ^ alkoxycarbonyl include ^ G ^ -G ^) alkoxy _T (C ^ -Cjθ) -alkyl such as methoxymethyl, ethoxymethyl, isopropoxymethyl, and the like, hydroxy-C ₁ -C θ ^) alkyl, such as hydroxymethyl and hydroxyethyl, and (C ^ -C ^ θ) alkoxycarbonyl-substituted (C ^ -C ^ θ) alkyl such as methoxycarbonylmethyl, ethoxycarbonylethyl, isopropoxycarbonylmethyl and target. butoxycarbonylmethyl.

The term (C 1 -C 6 -alkylene) means wherein n is 4 to 5

8, preferably n is 6 to 8.

-10Expression (θ ₄ -Οθ) alkylene means - (0¾) -4θΗ = ΟΗ) ^ - (0¾) | wherein g and i are independently 1 to 5 and h is 1 or 2, including, for example, cis- and trans- -OH ₂ EH = GH-GH ₂ -, -CH ₂ -OH = OH-OH or -CH ₂ -C ₁ -CH = CH-CH ₂ -, -CH ₂ CH = CH-CH ₂ -CH ₂ CH ₂ -, CH ₂ -CE ₂ -CH ₂ -GH = CH-CH ₂ -CH ₂ -, -CH ₂ CH ₂ -CH ₂ -CHxCH-GH ₂ -,

-CH ₂ -CH = GH- (GH ₂ ) ₄ -, -0Η ₂ αΗ ₂ 0Η = 0Η- (σΗ ₂ ) ^ -, (ΟΗ ₂ ) ₃ -ΟΗ = ΟΗ- (ΟΗ ₂ ) ₂ -, - ( CH ₂ ) ₄ Gřř = Gff CH ₂ -, -CH ₂ -CH ₂ GH- (GH ₂ ) ₅ -, -0¾-0¾-0 ^ 011 (0¾) ₄ ~, (σΗ2) ₃ -σ »= σΗ (σΗ ₂ ) ₃ - or - (CHPG-CHsCH-CRg-.

The term (O ₄ -C 8) alkynylene means - (O 3) (O = O) -O 3) -, wherein t is 1 to 5 and s is 1 or 2 and examples thereof include -CHg-C 1 -CHg-, - ( 0¾) y 0 = 0-0¾-,

-CR ₂ -C = G-GR ₂ Cl 2 -C = CG 2 -, - (0 ') 0 - 0 = 0- (0') 1, J 2 -CaC- (oh ₂ ) ₄ -c = o-ch ₂ -, - (oh ₂ ) ₃ -0 = 0-0- (0¾) ₂ - _ø - (oh ₂ ) ₂ -0 = 0- (0¾) ₃ -CH ₂ -O = O- (OH ₂ ) ₄ -, - (0¾) ^ 05.0-0¾., -. (OH ₂ ) ₄ -C = C- (C ^ ₂ , - (CR ₂ ) ₃ -0xC- (CR ₂ ) ₃ - (CH ₂ ) ₂ - C = G- (CH ₂ ) ₄ - or

-oh ₂ -c = c- (ch ₂ ) ₅ -.

The term (C 1 -C 6) alkyl means methyl, ethyl, n- and isopropyl groups.

Expression. (C1-C6) alkyl, denotes straight and branched chain alkyl groups of one to ten carbon atoms, (C1-C6) alkyl groups are preferred.

The term (O-O-O) perhaloalkyl means a (O-O-O) alkyl group wherein each hydrogen is replaced by a halogen, in particular F or O1, preferably (C1-Og) perhaloalkyl; more preferably perchloromethyl, perfluoromethyl and perfluoroethyl.

The term (C ₁ -G ₁ θ) alkylthio means linear and branched alkyl groups of one to ten carbons wherein carbon is monovalently bonded to -S-, e.g. ₍₃ 0H) -0 H ₂ N 3, 0¾¾ ^. and (CH ₃ ) ₂ OHS-. Preferred are (C 1 -C 6) alkylthio groups.

(11) The term (C 1 -C 8) alkylsulfonyl "means straight and branched alkyl groups of one to ten carbon atoms, wherein the carbon is monovalently bonded to SO ₂ - eg, CH ₂ SO ₄ -, C ₂ H 4 SO _2, and (O) are preferred. C ₁ -C 8 alkylsulfonyl groups.

T preferred compounds of the invention wherein

or

is GB'R * preferably -CH ₂ -, -O (O ') - ₂ or -GHC ₂ H- ₅ and Q is hydrogen, halogen, especially chlorine or fluorine. Other preferred compounds of the invention include those wherein the dotted line in Μ-1a 11-4 represents a double bond, i.e., where M is or _j 1 _(Cfy m + n is preferably 2 or 3 and A is 0.

The compounds of the invention have been found to be active against ether-resistant RNA viruses, i.e. picornaviruses, which include enteroviruses and rhinoviruses. Snter-viruses

They summarize viruses that are associated with the common cold and some other respiratory diseases. More than one hundred serotypes are identified. Although the compounds of the present invention are not active against all rhinoviruses, they are active against a large number of them, including the following rhinoviruses 1A, 2 ^ 3,4,5,7,9,14,15,21,36,39,41 The compounds of the present invention are also active against enteroviruses such as poliovirus-2-, coxsackieviruses A9, A21 and B1 and Echo 5,6 and 11.

Further, the compounds of the invention exhibit activity when tested in in vitro activity experiments. The first in vitro antiviral assay performed with the compounds of the invention is a plaque reduction assay that measures the ability of the compounds to neutralize viral infectivity, eg picornavir infectivity. In the anti-poliovirus-2 assays, the values of the compounds of the invention were about 0.008 to about 2.0 micrograms / ml. The IC5Q value in all antiviral tests is the concentration? test compounds in micrograms per milliliter / µg / ml, resulting in a 50% reduction in plaque-forming units compared to the untreated control.

The second in vitro assay was a modified, premix plaque reduction assay in which the virus and test compound were mixed and incubated at 37 ° C for 1 hour prior to overlaying with agar medium. The active compounds of the invention had a ΙΟΙΟ in this modified plaque reduction premix assay, from about 0.01 to about 3, ^for micrograms / ml against poliovirus, about 0.05 to 5 micrograms / ml against human rhinovirus 3, and about 0 , 8 to 5 microgram / ml against A9 coxsackie virus.

The plaque reduction assay was performed according to Woodsw

M.G et al., Antimicrob Agent Chemother (19 ^ 9), vol. 2069-20T4 and involves overlaying HeLa cells with agar medium containing measured concentrations of the test compound, followed by uptake of the virus and then incubating for 72 hours. The resulting plaques are stained and measured to determine direct inhibition of viral growth as seen from plaque reduction compared to control. .

the codified premix plaque reduction assay measures the ability of a compound to directly inactivate the virus itself and is considered more sensitive because its ability to more clearly limit the effects of neutralizing viral growth between compounds that are very close to the standard plaque reduction assay described by Woods et al.

The compounds of the invention were tested for antiviral activity in 1) primary in vitro studies with poliovirus-2 by measuring thermal stability, kTT antiviral activity, kTT therapeutic index of cytotoxicity and plaque reduction in premix, 2) kTT-baseline enteroviruses such as Echo 4,6 and 11 and coxsackieviruses A21,31 and A9 (3) in HeLa cell viability and 4) in an in vivo mouse poliovirus encephalitis model.

Based on these assays, preferred antiviral compounds represented by the following structural patterns Ia to Ig were identified:

-14Arj -O-M-O-AjTg

Compound 1a

[0057] Ib

Ic

Id

-eHr-O-eHr- ^c / ^H cc

H, CH, Ie

If ig -CHgCaCCHz-CHz- O- CH ^{CH c} HrO- 2ΌΙ

Cl

Compounds of Formulas Ia-Ig in Primary Screen to

1) (a) poliovirus-2 had stability ΙΟ θ thermal stability <10 / µg / ml

b) therapeutic indices (MTT cytotoxicity / MTT antiviral)

- <.50; c) premix plaque reduction values <-10 / Ug / ml

2) IC ₅₀ values <5.0 / µg / ml for 50% enterovirus 3) ΙΟΙΟ θ values of 50 / µg / ml versus HeLa cell viability model after 24 hours and 4) show oral activity in an in vivo mouse polyoviral model encephalitis.

The thermal stability test model is a measure of the ability of a compound to interact with a viral capsid and alter its characteristics to inactivate and render it incapable of causing infection. The thermal stability test was performed according to Tisdale M. et al. on «I. Antimicrob.Chemother (1984), vol.14, dod. A, 97-105.

The MTT antiviral and the MTT cytotoxicity assays were based on poliovirus-2 cells propagated and titered in He-La cells in accordance with the procedure _of Mosmann, T. J.Immunologicals Methods (1983) sv.65 55-63.

The MTT antiviral assay measures the ability of a virus to infect and disrupt tissue cell culture in vitro.

The MTT cytotoxicity assay measures the ability of a chemical synthetic compound to disrupt cells and render the cells incapable of promoting viral replication in vitro.

The therapeutic index is the ratio of MTT cytotoxicity to MTT antiviral activity in HeLa cells based on an antiviral assay with a virus such as poliovirus-2 for 24 hours.

The IC 50 value of the compounds of the present invention is determined by measuring the concentration of the compound that it inhibits

-1650% virus growth without disrupting tissue cell culture in vitro, makes these cells incapable of promoting growth.

iflodel oral murine poliovirus encephalitis was measured using a solution of the compound, eg, in corn oil or a colloidal suspension of the compound in corn oil, according to the McKinlay procedure, A.A. a spo. Antimicrob Agents Ohemother. (1986), Vol. 29, 30-32.

The compounds of the invention may be administered by any conventional route of administration, and in such a manner an antiviral effective amount of a compound of the invention is administered. The dosage may vary depending on the assessment of the patient's condition by the physician, the hazard of the conditions being treated and the compound employed. Determining the appropriate dose for a particular situation is in the hands of the physician. Treatment may begin with small doses that are less than the optimal dose of the compound. Thereafter, the dosage could be increased in small portions until the optimum effect under the circumstances is reached. Usually, the total daily dose may be divided and administered in portions throughout the day, if desired.

Depending on the route of administration, a dose of about 0.5 to about 1000 mg / kg body weight per day may be administered to provide antiviral activity. For example, dosages from about 0.5 to 400 mg / kg of body weight per day, preferably 0.5 to about 200 mg / kg of body weight may be used for oral administration, and for parenteral administration, e.g. intravenously, dosages of about 0.1 to about 20 mg / kg body weight.

On topical administration, the amount of compound administered varies widely with the amount of skin to be treated, as well as the concentration of active ingredient applied to the affected area.

The compounds of the present invention may also be administered by oral inhalation or intranasally. Typically, the compounds of the invention may be dissolved or disoerged in a pharmaceutically acceptable carrier suitable for use in a nebulizer and / or metered dose inhaler. Pharmaceutically acceptable carriers include, for example, water, saline, ethanol, and the like, which form a solution or suspension suitable for administration by the oral inhalation route in accordance with the present invention. If desired, the pharmaceutical composition suitable according to the present invention may also contain small amounts of non-toxic excipients such as melting agents, emulsifying agents, preservatives, stabilizers and pH buffering agents. The preparation of these pharmaceutical formulations is well known to those skilled in the art, see, eg, Remington's Pharmaceutical Sciences Mack Publishing Co., Easton PA 15, published (1975).

The compounds of the invention may also be deliverable transdermally for systemic distribution. The transdermal formulations may take the form of creams, lotions and / or emulsions and may be included in a matrix or reservoir type transdernal patch, as are conventional in the art for such purposes.

For preferred oral administration, the compounds of the invention are typically formulated into tablets, capsules, elixirs, solutions, suspensions, and preferably solutions. For parenteral administration, they may be formulated into solutions or suspensions. The compounds of the invention may also be formulated in topical formulations such as lotions, creams, ointments, sprays and mechanical delivery devices, e.g., transdermal.

Typical pharmaceutically acceptable carriers for use in the above-described compositions are, for example: sugars such as lactose, starches such as corn starch, cellulose and de-derivatives such as sodium carboxymethyl cellulose, ethyl cellulose and methyl cellulose, vegetable oils such as corn oil and β. or (S-cyclodestrins or hydroxyalkylated cyclodextrin derivatives as well as other carriers well known in the art. Liquid pharmaceutical preparations may also be advantageously formulated in solution with an appropriate amount of hydroxypropyl-α, γ- or β-cyclodextrin having 2 to 11 hydroxypropyl groups per molecule of cyclodextrin, polyethylene glycol, eg PEG-200 or propylene glycol, and these solutions may also contain water Pharmaceutical formulations in the form of (aqueous) solutions suitable for oral use may be prepared by adding a compound of formula I, II or III to a pharmaceutically acceptable carrier such as hydroxypropylated cyclodextrin in water and by adding suitable colorants, flavors, stabilizing agents, sweeteners, solubilizing and thickening agents, if pharmaceutical preparations in the form of aqueous suspensions suitable for oral administration are desired, they can be prepared by dispersing the active ingredient in finely divided form in water. Particularly preferred aqueous pharmaceutical preparations may be prepared from compounds of formula I, II or III or together with hydroxypropyl -? - cyclodextrin in water. The use of derivatives or .beta.-oxycodextrins, for example hydropropyl-.beta.-cyclodextrin, is described in

U.S. Pat. No. 4983586, Pith U.S. Pat. No. 4727064, and Janssen. Pharmaoeutical International Patent Application No. PCT / EP 84/00417.

The pharmaceutical compositions of the present invention may be prepared by mixing a pharmaceutically acceptable carrier, e.g., hydroxypropyl-N-cyclodextrin, with water and adding a virally effective amount of the drug of the present invention to the resulting medium. The solution thus formed is filtered and optionally the water can be removed by known methods, for example by rotary evaporation or lyophilization. The preparation of the solution can be carried out at a temperature of about 15 to 35 ° C. Water is normally sterilized water and may also contain pharmaceutically acceptable salts and buffers such as phosphate or citrate as well as preservatives. The polar ratio of the antiviral compound of formula I to the hydroxypropyl - / cyclodextrin is about 1: 1 to 1:80, preferably 1: 1 to 1: 2. Normally, hydroxypropyl-β-cyclodextrin is present in molar excess. The formulations may also contain preservatives, aerosol propellants and coloring, thickening, dispersing, emulsifying, wetting, stabilizing and buffering agents.

The dose of the compounds of the invention to be administered is dependent, according to the judgment of the physician, on many factors, such as the age and weight of the individual being treated, the route of administration, the potency of the compound administered, the indication for which the drug is administered and

Typically, a preferred daily dosage for treating viral infections will be administered orally, from about 0.5 mg / kg ^r to about 200 mg / kg in single or divided doses, with about 1.0 mg / kg to about 60 mg / kg as a dose. preferred.

Compounds of the invention represented by Formula 1, H or III are prepared according to Reaction Schemes A, 3 and 0 using commercially available starting materials and simple tchemical reactions.

Scheme A. HO-X-OH -> LG-her-LG

12

2. Ar ^ OH + LG-2I-LG - 3 '. Ar ^ O- ^ i— ^ G

-203. Ar ₂ OH + 14 »Ar ι Ο — Μ — Ο — Αγ ₂ I

For example, compound 11 is reacted with mesyl chloride in the presence of a base such as triethylaraine (TEA) in an aprotic solvent such as Cl 2 Cl 2 at 0 to 20 ° C to form compound 12i by reacting the mesylate with NaI to give the diiodide compound 12.

Phenol 10, e.g., 2-chloro-4-methoxyphenol, is reacted with compound 12 wherein LG is a leaving group such as Br, I, mesylate or tosylate in the presence of an alkali metal hydroxide such as NaOH. Reaction # 2 is carried out at a temperature of about -20 to; 6 ° C in an inert organic solvent such as dimethylsulfoxide (DMSO), dimethylformamide (DMF) or tetrahydrofuran (THF). Compounds of formula 14 are isolated by the addition of water and the crude product is purified by crystallization and / or column chromatography. Compound 14 is reacted with phenol 16 under reaction conditions similar to those used for reaction # 2 to give the compound of formula 1.11 or III. Scheme A or B applies when compounds 10 and 16 are different.

Scheme 3 · ° <

MeO ‘z

CHg

O-Aq ^DMF ΜθΟ

Scheme B is particularly preferred for preparing compounds of Formula I, II or III wherein M is -CH ₂ - ^CH 2 "and Ar and Ar ₂ are different. Compounds 20 wherein Lg is Br are commercially available. Compound 20 wherein Lg is mesylate or chlorine is prepared by reacting commercially available methyl 4- (hydroxymethyl) benzoate with mesyl chloride. Reaction of 20 with Ar ₁ OH is carried out as described in Scheme A to give compound 22. Reduction of 22 with a metal hydride such as LiAlH 4 in an aprotic ether such as THF affords benzyl alcohol 23 (not shown) which is converted to mesylate 24 standard poytupy. Reaction of 24 with the phenol sodium Ar ₂ OH in e.g. DMF provides compounds of formula L, II or III.

In cases where compounds 10 and 16 are identical, Scheme C applies.

22Schema C

2 Ar ₁ 0H + g m-2 1-Ig

Scheme D

The preparation of compounds of formula I, IX or III is also possible by the following synthetic steps using standard chemical reactions and known or commercially available starting materials well known in organic synthesis.

ch ₂ oh scheme C

Af ₁

AND,

-OAr,

2.

HOCH ₂

2) Ar, OH / NaOH

DMF

1) MsCl / Iirage Ah

A = S o O

CH3O2C

(CH ₂ ) ₂ OH

DMF

-241) B ₂ H ₆

2) MsCl / TEA

3) Ar ₂ OH / NaOH

Ατ, ΟίΟΗ ^ ζ ·

C.

CH 3 O-Afg

1) LiA1H4 ‘

2) MsCVTEA

CHjOMs

Ατ, ΟΗΖ

NáOH

-257.

NaBHa with chema C

AR2O

R / S rz:

OAr ₂

N ° 2 / ~

ArgO-CHg -Z y ”0Η ₂ Ο · Αγ i

F

The reduction in reactions D-2,3,4,5,6,7 and 8 are described in H.O.House, Synthetic Beactions, 2nd Ed. W.A. Benjamin lne. 1972. Sandmeyer's reactions in D-11 are described by March in Advanced Organic Chemistry: Reactions, Mechanisms and Structure McGraw-Hill, West York 1968, pp. 553-554.

Separation of the products of reactions 8, 9, 10 and 11 in Scheme D may be accomplished by standard chromatographic techniques such as thin layer chromatography, column chromatography or vaso-pressure liquid chromatography.

The separation of HO-M-Off compounds having chiral centers prepared by reactions 5, 6 and 7 in Scheme D can be resolved into individual enantiomers having the R or S absolute configuration using standard resolution techniques.

For an overview of cleavage techniques, see, e.g., S.H-rWilen, Top. Stereochem., 107 (1971); W. H. Wilen, A. Collet and J. Jacques, Tetrahedron 33, 2725 (1977); A. Collet, M. J. Brienne and J. Jacques, Chem. Rev. 80,21 5 (1980); J. Jacques, A. Collet, and S. H. Wilerti, Enantiomers Racemates and Resolutions, Wiley University, New York, 1981.

Compounds of reaction 1 of Scheme D e.g.

HOCHg

CH 3 OH or reaction 3, eg (A = O) (CH 3) OH can be hydrogenated (eg H ₂ / Pd) to saturated molecules and those molecules which are optically active can be resolved as described above.

The structural formulas of the compounds of the Examples were determined by PNMR and mass spectrum analysis.

DETAILED DESCRIPTION OF THE INVENTION

Examples 1-5

O — M- O

IV

Example

2-Cl

Table I

X

4-CH3O

M

- (CH ₂ ) e - (CH ₂ ) s - (CH ₂ ) t -ch ₂ -c = c-ch ₂ Example 1

Add 2 g of 6- (2-chloro-4-methoxyphenoxy) hexyl-1-iodide (prepared according to the procedures of Example 2 (a) 7.M.Giri javallabhana et al., U.S. Patent 4,851,423, issued July 25, 1989 and Diana; (1985) vol. 28, pp.748-52) to a mixture of 2 g of 2-chloro-4-methoxyphenol and 0.05 g of NaOH in 10 ml of DMF. The reaction mixture thus formed was stirred overnight. The reaction mixture was partitioned between CEL 3 Cl 2 ^and water. Orgs. The organic phase is separated and the solvent is evaporated to give the crude product. The crude product is purified by chromatography

-29silikagelu eluting with 100% CH2Cl2 ^to give 1.29 g of 1,1 / 1, 6-hexanediyl bis (oxy) / bis / 2-chloro-4-methoxybenzene /.

Example 2

The procedure of Example 1 is followed except that the hexyl 1-iodide of Example 1 is replaced with an equivalent amount of 5- (2-chloro-4-methoxyphenoxy) pentyl-1-iodide (prepared according to Example 16 (a) of US Patent 4851423). / ·

Example 3

The procedure of Example 1 was followed except that the hexyl-1-iodide of Example 1 was replaced with an equivalent amount of 5- (2-chloro-4-methoxyphenoxy) heptyl-1-iodide (prepared according to Example 15 (a) of US Patent 4851423). /.

Example 4

1.23 g of 1,4-dichlorobutine-2 is added to a mixture of 3.5 g of 2-chloro-4-methoxyphenol and 1.8 g of a 50:50 (wt / wt) mixture of NaOH: 4 in 30 ml of DMF. . The resulting mixture was stirred overnight at room temperature. The crude product was purified according to the procedure in Example 1 to give 1,1 '- (1,4-butin-2-diyl bis (ox.y)) bis (2-chloro-4-methoxybenzene).

Example 5

2.14 g of trans-1,4-dibromobutene-2 are added to the mixture

3.5 g of 2-chloro-4-methoxyphenol and 1.8 g of a 50:50 (w / w) mixture of NaCl2O in 30 ml of DMF. The mixture was stirred at room temperature overnight. The crude product was purified according to the procedure of Example 1 to give 1,1 '- [1,4-trans-butene-2-diyl bis (oxy)] - bis - [2-chloro-4-methoxybenzene].

-30Example 6

To a stirred mixture of 10.0 g 2-chloro-4-methoxyphenol and 1.5 g NaOH in 50 ml DMF was added 7.0 g. . 300 ml of water are added and the precipitated crude solid is filtered off. The crude product was purified by recrystallization from methylene chloride to give 9.12 g of 1,1 '- [1,4] phenylene bis (methyleneoxy)] - bis (2-chloro-4-methoxybenzene) as a pure compound.

Examples 7-14

According to the procedure of Example 3, substituting 2-chloro-4-methoxyphenol with the appropriately substituted phenol and

-dibromo-p-xylene with a suitable dibromide, the corresponding products are obtained.

Example δ. X ...... X OF 6 2-CI 4-CH3O H 7 2-CI 6-CI H 8 2-CI 4-CH3 H 9 2-F 4-F H 10 2-CI 5-CH3 H 11 2-CI 4-CH3 H 12 2-CI 4- _{(CH3) 2} CHO H

M

Η

Η

-33Examples 15a-x

Example.;. . ¥ M X X 15a 4-CH 3 O-2-Cl - CH 2 2-CI 6-CI 15b 2-Cl 4-CH 3 O- -CH 2 ^ 5 ^ ~ ^CH2 2-CI 5-CI 15c Oh <5> _CH2 2-CI 4-CI 15d - CH <Q) HCH ₂ 2-F 6-F 150 —CH2 - / 5 --CH2 2-F 5-F 15f '—CHz- ^ O ^ -CHg 2-F 4-F 15g · -CH 2 -CH 2 -CH 2 2-CH3 5-CH3 15h -CH 2 -? O? -CH 2 2-CH3 4-CH3 15i * ~ CHg ~ ^ O ^ ~ ^CH2 2-CH3 6-CH3 15j —CH2 --CH2 --CH2 2-CI 4-CH3 15k · · -CHt -ζθ ^ - (0-2) ₂ - 2-CI 6-CI 151 -CHa - <O> (CH, _2- 2-CI 5-CI

15m • “CH; - (-) - (082) 2- 2-Cl 4-CI 15η n -CH ₂ -? Q? - (CH 2) ₂ - 2 -Cl 4-CH3O 15ο H • -CH ₂ -? O? - (CH ₃ ) a-2-F 6-F 15ρ 2-CI 6-CI -CH 2 -CH 2 CH 2 -CH 2 -2-Cl 4-CH3O 15q 2-CI 5-CI -CH 2 O 4 -CH 2 J 2 -Cl 4-CH3O 15r 2-CI 4-CI -CH 2 O 2 - ( ^CH 2> 2- 2 -Cl 4-CH3O 15s 2-F 6-F -CH 2 -CH 2 -Cl 2 -Cl 4-CH3O 15t 2-F 5-F -CH3- (CH3d-2-Cl 4-CH3O 15u 2-F 4-F -CH 2 O- (R 2) 2 - 2 -Cl 4-CH3O 15v ^ -2-CH3 6-CH3 -CH 2 - @ CH 2 - 2 -Cl 4-CH3O 15w _2-CH3 5-CH3- -CH 2 -CH 2 -CH 2 -Cl 4.CH3O 15x 2-CH3 4-CH3 ² ' ^CI 4-CH3O

-35Example 15a

A. 5 g of 2-chloro-4-methoxyphenol was added to a mixture of g, n-dibromo-p-xylene in a stirred mixture of 2.5 g of 50:50 (w / w) and 50 ml of DMF. The resulting mixture was stirred for 4 hours. The reaction mixture was partitioned between methylene chloride and water. The organic layer was separated and the solvent was removed on a rotary evaporator to give a solid residue. The residue was purified by silica gel column chromatography using pure hexane to pure methylene chloride as eluents to give 8 g of 1- (4-bromomethylbenzyloxy) -2-chloro-4-methoxyphenyl ether.

B. To a solution of 0.50 g of 2,6-dichlorophenol in a mixture of 0.12 g of H _and OH in 5 ml of SMF was added 0.50 g of the phenyl ether from step (A) and stirred at room temperature for 4 hours. Water (50 ml) was added to the reaction mixture, and the resulting crude precipitate was filtered off. The crude precipitate was purified by crystallization from methylene chloride to give 350 mg of 2-chloro-1- [4 - [(2,6-dichlorophenoxy) methyl] phenyl] methoxy] -4-methoxybenzene as a pure solid.

Examples 15b-x

The procedure of Example 15a is followed except that in steps A and 3 of Example 15a it will replace phenols and HO-M-Off to produce the desired products.

Examples 16.17

-36Table

Example

δ.

-CH

Hz'

N

2-C117

2-C14-CH = CH-O4-O2,5-pyridindiylbismethylen ² »6-pyridindiylbiSímethylen

Example 16

(a) 50 ml of thionyl chloride are added to 25 g of pyridine-2,5-dicarboxylic acid and the mixture thus formed is heated at reflux for 6 hours. The volatiles were removed by distillation in vacuo to give the crude diacid chloride. The flask containing the diacid chloride is immersed in an ice bath and 100 ml of absolute ethanol are added. 30 ml of triethylamine is slowly added to the stirred reaction mixture, and stirring is continued for 1/2 hour. Ethyl acetate / water was added to the stirred reaction mixture, and the organic layer was separated. The solvent was removed to give the crude product. This crude product was recrystallized from hexane / methylene chloride to give 25 g of pyridine-2,5-bis (ethyl carboxylate)

b) Slowly add 9 g of the Na 3 H 4 solution of the diester from step

(a) in 150 ml of ethanol. 13.5 g of CaCl2 as a solution in 150 ml of ethanol are added to the stirred reaction mixture and stirring is continued overnight. 12 g of sulfuric acid are added and the solid formed is filtered off. To adjust the pH, HCl is added and the pH is adjusted to about 4. All solvent is removed by rotary evaporation to give the crude product. The crude product was purified by crystallization from methanol to give 11 g of 2,5-cis (hydroxymethyl) pyridine as the HCl salt.

c) To a solution of 10 g of pyridine compound 16b and 32 ml (4 eq.) of triethylamine in 250 ml of methylene chloride in a reaction vessel immersed in an ice bath was added 11 ml (2.5 eq.) of C 6 H 5 Cl 2 using an injection pump. The reaction mixture thus formed was stirred 1/2 hour after the addition was complete. Partition between methylene chloride and water. The organic layer was separated and the solvent removed to give the crude product, which was purified by crystallization from methylene chloride / hexane to give 2,5-pyridinediyl-bis (methylene mesylate).

d) Following the procedure of Example 6 except that, ¹ st px.ylenem dibromo-equivalent amount of the bis-mesylate from Example 16c), 1,1 '- / 2,5-pyridinediyl bis (methyleneoxy) / - bis (2-chloro-4-methoxybenzene) as a pure solid.

Example ⁷ 1 7

The procedure of Example 16 was followed except that the acid was replaced with an equivalent amount of 2,6-pyridinedicarboxylic acid in step a) and was obtained in step

d) 1,1 * - [2,6-pyridinediyl-bis (methyleneoxy)] - bis (2-chloro-4-methoxybenzene) (23 g) as a pure solid.

-38Examples 18-20

X vn

Example

X Ϊ M 18 2-CI H 19 Dec 4-CH3 O H w 20 May II 2-NH 2 -C H n Progressing according to example 6 p the difference

2-chloro-4-methoxyphenol is replaced with an equivalent amount of the appropriate 3-hydroxypyridine and N, N -dibromo-p-xylene is replaced with an equivalent amount of 2,5-di (bromomethyl) pyridine to give the corresponding compound.

Example

C.

Y M 21 2-CI 4-CO ₂ Et 22nd 2-CI 4-HOCH2- w 23 2-C, 4-CH3OCH2 · « Example 21

The procedure of Example 6 is followed except that 6 g of cis -dibromo-p-xylene is added and 2-chloro-4-methoxy-phenol is replaced by 10.0 g of 2-chloro-4-ethoxycarbonylphenol to give 6-chloro-4-ethoxycarbonylphenol. 8 g of 1,1 '- [Ί, 4-phenylene-bis (methylexioxy)] - bis (2-chloro-4-ethoxycarbonylbenzene).

Example 22

5 g of the compound of Example 21 was reduced with a solution of 15 ml of 1 molar LiAl2O in THF at 0 ° C. The reaction mixture thus formed was stirred for 6 hours. 20 mL of saturated aqueous NH 4 Cl solution was added and the solid was filtered off, the solvent was removed from the filtrate to give the crude product. The crude product was purified by crystallization from CH 2 Cl 2 to give 3.6 g of 1,1 '- [1,4-phenylene-bis (methyleneoxy) fluoride (2-chloro-4-phenylmethanol)].

-40V

Example 23

To 1 g of the compound of Example 22 was slowly added 5.25 ml of N _and N / (Si). The reaction mixture was stirred for 15 minutes, 0.33 ml of CH 2 Cl 2 (undiluted) was added and the reaction mixture was stirred for 4 minutes. 200 ml of water was added and the crude product was collected by filtration and the crude product was purified by crystallization from GHgClg and hexane to give 750 mg of 1,1 * - [1,4-phenylene-bis- (methylenoxy)] - bis]. 2-chloro-4- (methoxymethyl) benzene].

Examples 24 and 25

a) Preparation of 1,4-di (bromomethyl) -2-chlorobenzene

A solution of 2.8 g of 1,4-dimethyl-2-chlorobenzene is heated at reflux temperature for 4 hours; 7.30 g of N-bromosuccinimide (N3S), 50 ml of Cl2C and 100 mg of benzoyl peroxide. Remove the solid floating on the surface of the reaction mixture and remove the CCl 2 under reduced pressure to form a residue.

The residue was purified by crystallization from hexane and silica gel column chromatography eluting with hexane to give 2 g of the title compound as a solid.

To a solution of 7.00 g (18.9 mmol) of 2-chloro-4-methoxyphenol and 1.58 g (19.8 mol) of NaOH (as a 50% aqueous solution) stirred at room temperature for 10 minutes was added 11.3 g. g (37.9 mmol) of the dibromo compound of step a). The reaction mixture thus formed was stirred at room temperature for 3 hours. The reaction mixture was placed in a refrigerator overnight. The reaction mixture was poured into 500 ml ^{of water and} 00 ^ y ^{^, and that} the formed mixture is stirred for 5 minutes. The organic layer is from <

Separate and wash with brine and dry the separated organic layer over magnesium sulfate. The solvent was removed under reduced pressure to give a residue. The isomers were separated on a silica gel column and the fractions containing pure compound by TLC were combined. The 200 MHz NMR and mass spectra of the above compounds were consistent with the proposed structures.

To a solution of 87.1 mg (0.535 mmol) of 2,6-dichlorophenol and 42.8 mg of NaOH (0.535 mmol) as a 50% aqueous NaOH solution, in 2 mL of DMF was added 100 mg (0.267 mmol) of Compound A from step b) . The reaction mixture thus formed was stirred at room temperature for 4 hours. Add water, 1N NaOH · and ETOAc to the reaction mixture and stir the mixture so formed 5 ^; minutes at room temperature. The organic layer was separated and washed with brine and the separated organic layer was dried over magnesium sulfate. The organic solvent was evaporated to give 133 mg of the title compound. 200 MHz NMR and mass spectra were consistent with the proposed structure? ·

d) Preparation o ₃ o ci

The procedure of step o) was followed except that an equivalent amount of compound B of step b) was replaced by compound A to give 130 mg of the compound mentioned above. 200 MHz NMR and mass spectra were consistent with the proposed structure.

43Examples 26-56

Example

IN M X Y 26 4-CH3O2-Cl CH 2 -Q-CH 1 « 2-CH3 6-CH3 27 Mar: o « 2-CH3O 6-Cl . n « 2-Cl 5-CI ?WITH - « « 2-Cl 4-C1 29 30 « 2-F 6-F

31 32 2-Cl ^CH 2 ^CH 2 -Q ^{2 'F} Cl h 6-F 33  2-CI 4-CI 34  2-CH3O 6-CI 35  2-CH3 6-CH3- 36 CH - "^ QV-tCHzlz ² · ⁰¹ 6- (CH ₃ ) ₂ CHO 37 CH 2 - ^ q - (ch ₂ ) ₂ ² - ^{c a} 6-CI 38 CH 2 - OCH ² - ⁰¹ a 5-CJ 39 CH 2 --O 4 - ( ^CH 2) 2 ² ' ^Cl 4-CI 40 CH2 --CH2 (CH2) 2 ² - ^F 6-F 41 CH 6 - O 2 - (CH 2) ₂ ^{2 -Fa} 5-F 42 CH 2 -? O? - (CH 2) ₂ ^{2 -Fa} 4-F 43 CH 2 - (CH 2) ₂ ^{2: CH} 3 6-CH3

-4544

_2-CH3

5-CH3

CH 2 (CH 2) ₂ ² - ^{CH 3}

4-CH 3 ch 2 —h 2 Qy - (CH 2) 2 Cl

2-CI

4-CH3O

2-CI

6-Cl CH2 - (o > - (CHzh

2-CI

4-CH3O

Cl

2-CI

4-CH3O _CH2 - (o) - (CH2) 2 ^:

2-CI

5-CI

2-CI

4-Cl

2-CI

2-F

5-F

2-F

4-F

_2-CH3

4-CH3O

6-CH3

4-CH3O

6-F

4-CH3O

4-CH3O

4-CH3O

54 _2-CH3 5-CH3 C * 2 - ^ OV '(CH2) ₂ ² * ^Cl Cl 4-CH3O 55 2-CH3 4-CH3 CH 2 - (O 1 - <CH 2) 2 ² ' ^CI α 4-CH3O 56 2-F 6-CH3O ^CH 2 - O 2 '( ^CH 2> 2 ² * ^F 4-CH3O

α

The procedure of Example 25 was followed with the difference that it was

-47a) Add 35.95 g (0.314 nol, 2 eq) allyltrimethylsilane and 38.6 mL, 2 eq) BF 2 etherate to a solution of 50 g (0.15 mol) β-D-ribofuranose tetraacetate in 500 mL dry 0Η ₂ · 0ΐ2 mixture thus formed was stirred at 25 ^Q C for 2.5 hours. 0.157 mol of alkyltrimethylsilane and 157157 mol of BF ^ etherate are added to the reaction mixture, and the mixture thus formed is stirred overnight. No starting material was detected by TLO. The solvents were removed under reduced pressure and the residue was subjected to preparative column chromatography on a silica gel column using EIOAC / hexane as eluent to give allyl triacetate.

b) 68.33 g (0.4945 mol, 3.0 eq) of powdered potassium carbonate was added to a solution of 49.5 g (0.1648 mol) of allyl triacetate from step a) in 500 ml of ethanol. The mixture was stirred at 25 ° C for 2 hours. The reaction mixture was filtered to remove excess potassium carbonate and the solvents were removed from the filtrate to give a foam. Dissolve the foam in 20 ml conc. HCl and 80 mL acetone over 10 minutes. The solution was diluted with additional acetone and stirred for 2 hours. Three equivalents of potassium carbonate were added and the resulting mixture was stirred overnight. Remove excess potassium carbonate by filtration and evaporate excess acetone. It comes

The organic layer was washed with water. Purification of the reaction mixture by silica gel column chromatography gave 3.5 g of less polar cis-all-alcohol-acetonide and

28.5 g of more polar trans-allyl alcohol-acetonide.

c) To a solution of 1 g (4.67 mmol) of the trans-allyl alcohol-acetoaid from step b) in 25 ml of CITgO1g, ozone was bubbled through -78 ° C (liquid nitrogen bath) until the solution was light blue. Flush rapidly with nitrogen gas. 5 ml of dimethylsalphide are added and the reaction mixture thus formed is heated under reflux for 3 hours. The solvents were removed under reduced pressure and the residue thus obtained was dissolved in 10 ml THF and 3 ml water. 176 mg (4.677 mmol) of NaBH4 were added. Stir for 2 hours. THF was removed under reduced pressure. 20 ml of water are added to the residue and the aqueous layer is saturated with sodium chloride. The aqueous layer was extracted with five 10 ml portions of ETOAC. The organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure to give 710 mg of product which crystallized on standing overnight. The 200 mHz NMR spectrum is consistent with the proposed structure.

d) To a solution of 700 mg (3.207 mmol) of the product of step c) in 15 ml of dry CH ₂ Cl ₂ and 1.16 ml (8.334 mmol) of triethylamine cooled to 0 ° C was added dropwise 595 µl (7.696 mmol) (2, 4 eq) CH 2 SO 2 Cl in 2 mL of dry CH ₂ Cl ₂ . The resulting reaction mixture was stirred for 3 hours and the temperature was slowly raised to 25 ° C. Add 25 mL of CH ₂ Cl ₂ and wash the organic layer with water and then brine. The organic layer was dried over sodium sulfate and the solvent was removed to leave a residue. To this was added 10 mL of dry LMSO. 2.3 g (0.01282 mol) of sodium 2-chloro-4-methoxyphenoxide were added to the obtained solution, and the reaction mixture was stirred for 48 hours. CH ₂ Cl _{2 was added} , the organic layer was washed with water and 10% NaOH in water, brine, and dried over sodium sulfate. The solvent was removed under reduced pressure to give a residue. This was purified by column chromatography on silica gel eluting with 50% CH ₂ Cl ₂ / hexane to 100% CH ₂ Cl ₂ . The 200 MHz NMR spectrum of the product obtained was consistent with the proposed structure.

0.1N HCVCH3OH 57D -a

57E

A mixture of 385 mg (0.7715 mmol) of the product of step d) in 40 ml of 0.1N HCl is heated at 70-80 ° C for 1.5 hours and stirring is continued overnight while the temperature is cooled to room temperature. The starting material still covers the bottom of the flask. 20 ml of CH 2 OH are added. The reaction mixture was heated at 70-80 ° C for 3.5 hours and a solution formed. Cool to room temperature, remove CH 2 OH and adjust the pH to 12 with NaOH and saturate with NaCl. 3 portions of ethyl acetate. The combined extracts are dried over; sodium sulfate and the solvent was removed under reduced pressure to give 345 mg of the diol. 20OMH3NMR and mass spectra were consistent with the proposed structure.

f) To a solution of 215 mg (0.4684 mmol) of the product of step

e) 307 µL (298 mg, 6 eq.) of HO (OCH 3) and 58.8 mg (0.2342 mmol, 0.5 eq.) of pyridinium p-toluenesulfonate were added in 5 mL of dry CH 2 Cl 2 and the reaction mixture was Stir overnight at room temperature (25 ° C). The reaction mixture was washed with aqueous sodium bicarbonate, water, brine, and the organic layer was dried over sodium sulfate. The mixture was purified by silica gel chromatography eluting with 10% EtOAc / hexane to 40% EtOAc / hexane. 160 mg of the desired compound is obtained (68% yield). The 200 MHz NMR spectrum is consistent with the proposed structure.

-51 (CH3CO4 O-) >>

140 [deg.] C

g) Heat a solution of 156 mg of the product of step f) in 10 ml of acetic anhydride at 140 ° C overnight. No starting material was present by TLC. The solvent was removed under reduced pressure. CH 2 Cl 2 was added to the residue and the organic layer was stirred with sodium bicarbonate for 2 hours. The organic layer was separated and dried over sodium sulfate. The solvent was removed and the residue was purified by silica gel column chromatography eluting with 75% CH 2 Cl 2 / hexane to give 40 mg of the desired product. 200 MHz NMR and mass spectrum were consistent with the proposed structure.

O — O58-100

X

Υ

Example 'W IN M X Y 58 2-CI 4-CH3O- ΎΤ 2-CI 6-CI 59 and and and 2-CI 5-CI 60 and and and 2-CI 4-CI 61 • and and 2-F 6-F 62 and and and 2-CH3 4-CH3 63 and and YJ 2-CI 6-CI 64 and and and 2-CI 5-CI 65 and and and 2-F 4-F 66 and and and 2-CH3 5-CH3 67 and and VJ 2-CI 6-CI 68 and and 2-Cl 5-CI 69 and and and 2-F 4-F - 70 and and and 2-CI 4-CH3O 71 2-CI 5-CI and 2-CI and 72 2-CI 6-CI and and and 73 2-F 4-F and and and 74 2-CI 6-CI (CH 2 K. {CH 2) _r and and

75 2-CI 5-CI and • a ⁷⁶ 2-CI 4-CI and and a 77 2-CI 4-CH3O and and a 78 and and and 2-CI 5

79 r R R 2-F 4-F 80 R R 0 2-F 6-F 81 2-CI 4-CH3O 2-CI 6-CI 82 R R 0 2-CI 5-CI 83 0 R 0 2-CI 5-CI 84 M R 2-CI 4-CH3O 85 2-CI 6-CI 0 0 w 86 2-CI 5-CI 0 0 0 87 2-F 4-F 0 2-CI 4-CH3O 88 2-CI 6-CI 0 0 89 2-CI 5-CI \_of 0 0 0 90 2-CI 5-CI 0 0 0 91 2-F 6-F 0 R 0 92 2-F 5-F 0 0 0 93 2-CI 4-CH3O 0 0 0 94 2-CI 6-CI 0 2-CI 4-CH3O 95 2-d 5-CI 0 0 0 96 2-F 4-F 0 R 0 97 _2-CH3 6-CH3 0 R 0 98 2-CH3 5-CH3 « 0 0 99 2-F 5-F 0 0 0 100 ALIGN! 2-F 6-F 0 R 0

The procedures of Examples 15 and 27 and Scheme A &apos; equivalent amounts of HO-M-OH will replace the diols and phenols of Examples 15 and 57.

-54If the pros ’101 to 120

101 2-Cl 4-CH3O CH ₂ S 2 2-Cl 6-Cl 102 R R ) _t R 2-Cl 5-CI 103 R R R 2-Cl 5-CI 104 R R R 2-Cl 4-CH3O 105 2-Cl 6-Cl R « R 106 2-Cl 5-CI R R « 107 2-F 4-F R 2-Cl 4-CH3O 108 2-Cl 6-Cl ch ₂ ^ 0 . _c \ CH 2) 2- R R 109 2-Cl 5-CI R 1 R R 110 2-Cl 5-CI R R R 111 2-F 6-F R R « 112 2-F 5-F R R R 113 2-Cl 4-CH3O R -. 'R R 114 2-Cl 6-Cl R 2-Cl 4-CH3O 115 2-Cl 5-CI R R • 116 2-F 4-F R R R 117 _2-CH3 6-CH3 R R R 118 2-CH3 5-CH3 R R R 119 2-F 5-F R R R 120 2-F 6-F R R R

The procedure of Examples 81-100 was followed except that an equivalent amount of HO-M-GH that had been hydrogenated with H ₂ / Pd was replaced to give saturated tetrahydrofuran in the dihydropyrandioles of Examples 81-100.

In a similar manner, the 2,5-furanediols used as starting materials in Examples 58-62 and 67-73 can be hydrogenated to give isomeric 2,5-tetrahydro-ydrofuran-diols which can be separated into pure compounds and then used to prepare other compounds in the of the invention · »

Example 121

a) Preparation of methyl 4-chloromethylbenzoate

To a solution of 100 mg (0.60175 mol) of methyl 4-hydroxymethyl benzoate in 6Q0 ml of CH ₂ C1 ₂ was added 109 ml (79.1 g) of TEA and the reaction mixture was cooled to 0 ° C. 55.0 ml (0.722 mol, 1.2 eq.) Of methanesulfonyl chloride in 150 ml of dry CH 2 Cl 2 are added dropwise over 2 hours. The reaction mixture was stirred until slowly warmed to temperature; room within 48 hours. TLC showed no remaining starting material. Water was added, the layers were separated and the organic layer was washed sequentially with water, saturated sodium bicarbonate and brine. The organic layer was dried over sodium sulfate. The organic solvent was removed under reduced pressure to give 98.45 g (88.6% of theory) of the title compound as a crystalline solid.

-56b) Preparation

CH ₃ OC

whose

Cl- QR Hr ° ^C - <Q "It is stirred with a mixture of 100 g (0.61324 mol) of 2,6-dichlorophenol,

24.5 g (0.6134 mol) of NaOH and 50 ml of anhydrous ethanol at 25 ° C for 1 hour. The ethanol was removed under reduced pressure to give 114 g of off-white sodium 2,6-dichlorophenoxide.

A mixture of 100 g of the product of step a) in 500 ml of dry DMF and 81.1 g (0.54168 mol) of NaI and 150 g (0.8108 mol, 1.5 eq) of sodium 2,6-dichlorophenoxide was stirred overnight · At room temperature. Water was added to the reaction mixture and a solid precipitate formed. To dissolve the precipitate, add OHgClg * CHgClg layers successively washed with four volumes of 5% aqueous NaOH solution, water and brine. The organic layer was separated and dried over sodium sulfate. The solvent was removed under reduced pressure to give 164.5 g (97.6% of theory) of the title compound. 200 MHz NMR spectra consistent with expected structure.

Whose

To a cooled solution of 5 g (0.016 mol) of the ester from step b) in 30 ml of freshly distilled THF was added 0.96 (0.0253 mol) LiAlH 3. in portions with stirring. According to TLC, the starting material is not present. The reaction mixture was cooled and treated dropwise with 1 mL of water, 1 mL of 15% aqueous NaOH, and 3 mL of water to form a granular precipitate. 2 g of anhydrous sodium sulfate was added and the mixture was stirred for 25 minutes. The precipitate was collected by filtration and THF was removed under reduced pressure. Thus, 3.9 g (80.6% of theory) of the title compound are obtained. The 200 MHz NMR spectrum was consistent with the expected alcohol structure.

-5d) Preparation of 2-chloro-4-methoxyphenol

To a solution of 250 g of 4-methoxyphenol in 600 ml of CHG1j was added dropwise over 3 hours 190 ml of SC2 Cl2 in 200 ml of CHCl3. The reaction mixture was stirred at 25 ° C for 18 hours. According to TLC, the reaction mixture contained no starting material. The solvent and SO 2 Cl 2 were removed under reduced pressure and the product was distilled under reduced pressure to give 210 g of the title compound. 200 MHz NMR was consistent with the proposed structure.

e) Preparation

To a solution of 131 g (0.4626 mol) of the product of step o) in 800 ml of dry CH3 Cl3 83.8 ml (0.60138 mol) of TEA was added at room temperature. 0 ° G dropwise 42.96 ml (0.555 mol, 1.2 eq.) Of methanesulfonyl chloride in 150 ml dry během ₂ Οΐ2 · over 1 hour ·

While stirring, the solution is allowed to slowly warm to 25 ° C over 48 hours. Water was added and the separated organic layer was washed with water, 10% aqueous NaOH, brine, and the organic layer was dried over sodium sulfate. The solvent was removed under reduced pressure to give 127.5 g (91.4% of theory) of the title compound. The 200 MHz NMR spectrum is consistent with the proposed structure.

f) Preparation

HE -58Mí _C mixture of 95.66 g (O, L1 71 mol) of the product from step e), 400 mL of dry DMF, 60.33 g (0.3805, 1.2 eq.) Of 2-chloro-4-methoxyphenol from step d) and 15.85 (0.3963 mol,

1.25 eq) of broken NaOH pellets at room temperature overnight. No starting material was detected by TLC in this mixture. ETOAo was added and the resulting layer was washed sequentially with 5 volumes of water, brine and the separated organic layer was dried over sodium sulfate. The solvents were removed under reduced pressure to give 130 g of crude product. The crude product was purified by recrystallization from anhydrous ethanol to give 112 g of the title product. 200 MHz NMR and mass spectrum were consistent with the structure of the expected product.

Claims (3)

PATENT N N''R O Κ ϊ 1. Compound of Formula I Ar ₁ -OMO-Ar ₂ (I). wherein Ar ₁ and Ar ₂ are each independently substituted phenyl or substituted pyridinyl, wherein the substituents of said phenyl or pyridinyl are independently selected from one, two or three halo (C ₁ -C ₁ ) alkyl, (C 1 -) C ^ Jperhalogenalkylů, (C ₁ -C θ ^) alkoxy, halogen, carbamyl, dialkylkarbamyl (C ₁ θjalkoxykarbonylu, oxazolinyl, and (C -G] a) alk.ylu substituted (C ₁ -C θ ^) alkoxy, hydroxy, or ( C ₁ -C ₁ θ) alkoxycarbonyl, (C ^ -Cgjalkylen, (C ^ -Cg) alkylene or (C ^ -Cg) alkynylene, 0 is oxygen, M-3 / M-4 -60R * is (C 1 -C 6) alkyl or H And is oxygen or sulfur, Q is selected from the group consisting of hydrogen, halogen, nitro, (C 1 -C 6) alkyl, (C 1 -C 6) perhaloalkyl, (C 1 -C 6) alkylsulfonyl, the dashed line in M-3 and M-4 between carbons 2 and 3, 3 and 4, and 4 and 5 means that the bonds between carbons 2 and J, and 3 and 4, and 5 and 6 may each be a single or double bond, n is 1 or 2, m is 1 or 2 p is 0 or 1 and or a pharmaceutically acceptable salt thereof. A compound according to claim 1, wherein M is M-1, i. 3. the compound of claim 1, wherein M is M-2, i. -61 CHg- 4. Compound according to Claim 1 where id is (C 1 -C 6) alkyl- * only. 5. Compound according to Claim 1 where M is (c ^ —Cg) alke— in n ^ len. 6. Compound according to Claim 1 where M is (C 4 -C _g) alki- n.ylen. 7. Compound according to Claim 1 where M is \ (CH2) _m \ ¹ A Ώ • • 8. Compound according to Claim 1 where M is A compound according to claim 1, wherein Ar 1 = Ar ₂ · -6210. A compound according to any one of the preceding claims wherein Ar ₁ and Ar ₂ are independently of each other 2,4,2,5 or 2,6-di-halogen- and 4- (C1-C6) alkoxy. A compound according to any one of the preceding claims, wherein Ar ₁ and Ar ₂ are each 4- (C ₁ -C 8) alkoxy) -2-halophenyl. A pharmaceutical composition for the treatment of viral infections comprising an antiviral effective amount of a compound according to any one of the preceding claims and a pharmaceutically acceptable carrier 13. Pharmaceutical preparation according to claim 18, characterized in that it is adapted for oral administration 14. Use of a compound of formula I according to any one of? of the preceding claims for the preparation of a medicament for treating or preventing picornavirus infections in mammals in need of such treatment or prevention. A process for the preparation of a compound of formula (1) according to any one of the preceding claims, comprising the steps of A. a) reacting a compound of formula Ar 4 OH with LG-M-LG in the presence of an alkali metal hydroxide to form a compound of formula AtjOM-LG, b) reacting the product of step a) with Ar ₂ OH in the presence of an alkali metal hydroxide to form a compound of formula I according to claim 1, wherein Ar ₁ , Ar ₂ and M and Q are as defined in claim 1 and LG is a leaving group; -633. reacting one equivalent of LG -? - LG with two equivalents of Ar ^OH or Α ^Η in the presence of an alkali metal hydroxide to form compounds of formula I according to claim 1, wherein Ar ^, Ar ^, and O are as defined in claim 1, and LG is a cleavable group.